Experimental Cancer Drugs May Halt Events That Lead To
Cardiac Hypertrophy and Heart Failure

(Philadelphia, PA) - The events that lead to cardiac hypertrophy,
the enlargement of heart muscle cells, may be stopped by histone deacetylase
(HDAC) inhibitors, a class of therapeutic agents currently under development
as cancer drugs, according to researchers at the University of Pennsylvania
School of Medicine. Cardiac hypertrophy is one of the leading causes of
congestive heart failure, the most common diagnosis given for discharged hospital
patients in the United States.

In the September issue of Journal of Clinical Investigation, the Penn
researchers suggest novel genetic causes for - and new therapeutic agents against
- cardiac hypertrophy and heart failure. Furthermore, the researchers demonstrate
that anti-HDAC drugs can block the development of hypertrophy in animal models.

"In our studies, we determined that valproic acid, an HDAC inhibitor used to
treat seizure disorders, is effective in preventing heart muscle cells from
enlarging," said Jonathan A. Epstein, MD, Associate Professor in the
division of Cardiovascular Medicine within Penn's Department of Medicine. "In
recent years, drug companies have also begun developing more advanced HDAC inhibitors
to treat cancer. These HDAC inhibitors may be among the first known medications
to prevent cardiac hypertrophy."

Cardiac hypertrophy can be a healthy physiological response to events, such
as aerobic exercise, where heart cells grow larger like any other well-conditioned
muscle. Pathological hypertrophy, however, may result from genetic mutation
or, most commonly, from the consequences of an unhealthy cardiovascular system.

"The exertion of pushing blood against high resistance in the setting of high
blood pressure or overcompensation for heart muscle lost during a heart attack
can cause heart muscle cells to enlarge," said Epstein. "While it might be helpful
at first, hypertrophy can increase the stress placed on the heart and begin
a downward spiral of events that ultimately leads to heart failure. Despite
the fact that this is a common every-day problem for clinicians and patients,
we have very few, if any, medications that are directed at halting the cellular
events responsible for this deterioration. That's why our present studies are
so encouraging."

Unlike most cells, cardiac muscle cells largely stop dividing after birth and
only then grow larger through hypertrophy. The disease form of hypertrophy is
associated with the re-activation of a genetic program that normally stops soon
after birth. "Mature heart cells are naturally programmed to be anti-hypertophic,
but mutation or the cumulative effects of cellular stress seems to restart a
program of events that we've only seen in developing fetuses, " said Epstein.

Epstein and his colleagues previously linked fetal cardiac development to a
protein called Hop, which is thought to control heart cell growth. Hop is abundant
in fetuses and newborns, but less so in adults, where it seems that the over-production
of Hop overrides the cell's normal genetic programming. Hop does so by recruiting
HDAC, which blocks a set of genes that normally protect the heart from hypertrophy.
In effect, HDAC unlocks genes that have been kept hidden since birth.

"This genetic control of cell growth is why HDAC inhibitors also make for promising
anti-cancer drugs," said Epstein. "Although we do not know for certain what
this genetic program entails, it clearly results in severe cardiac hypertrophy
and premature death in animal models."

The elucidation of these chemical pathways and genetic programs will offer
more new targets for the treatment of congestive heart failure, Epstein believes.
The Penn researchers hope to continue to study HDAC inhibitors and their possible
therapeutic roles in clinical trials to prevent hypertrophy in at-risk patients.

Contributing Penn researchers include Hyun Kook, John Lepore, Aaron D. Gitler,
Min Min Lu, and Victor Ferrari from the Division of Cardiovascular Medicine
and Rong Zhou from the Department of Radiology. Other contributing researchers
include Wendy Wing-Man Yung and Joel Mackay from the University of Sydney and
Peter Gruber from The Children's Hospital of Philadelphia.

Funding for this research was provided through grants from the National Institutes
of Health.

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